Department of Medicine IV, Eberhard-Karls-University Tübingen, Tübingen, Germany.
Lancet. 2012 Jun 16;379(9833):2270-8. doi: 10.1016/S0140-6736(12)60479-6. Epub 2012 Jun 9.
Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone.
We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, 2011. Patients aged 18-85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA(1C)) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA(1c) concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-005448-21, and ClinicalTrials.gov, number NCT00359762.
We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12·4 [95% CI 6·2-18·6], hazard ratio 0·748 [0·623-0·899]; p=0·002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA(1c) concentration of less than 7% (p<0·0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6·5% and less (p=0·0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0·0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0·0001), nocturnal (p=0·007), and non-nocturnal (p<0·0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0·0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter.
These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone.
Eli Lilly and Company; Amylin Pharmaceuticals.
2 型糖尿病患者的血糖控制随时间推移逐渐恶化。在一线治疗药物二甲双胍治疗失败后，对于需要升级治疗的患者，可供选择的方案仍存在争议。我们比较了在单独使用二甲双胍血糖控制不佳的 2 型糖尿病患者中，添加艾塞那肽与格列美脲治疗对血糖控制的持续作用。
我们在 2006 年 9 月 5 日至 2011 年 3 月 29 日期间在 14 个国家的 128 个中心进行了一项开放性、随机对照试验。年龄在 18-85 岁之间、单独使用二甲双胍血糖控制不佳的 2 型糖尿病患者，通过计算机生成的随机序列被随机分配接受每日两次艾塞那肽或每日一次格列美脲作为二甲双胍的附加治疗。随机分组按照预先设定的糖化血红蛋白（HbA1c）浓度分类进行分层。主要结局是血糖控制不佳和需要替代治疗的时间，定义为治疗最初 3 个月后 HbA1c 浓度大于 9%，或治疗最初 6 个月后连续两次就诊时 HbA1c 浓度大于 7%。分析是根据意向治疗进行的。这项试验在 EudraCT 注册，编号为 2005-005448-21，在 ClinicalTrials.gov 注册，编号为 NCT00359762。
我们将 515 名患者随机分配到艾塞那肽组，514 名患者分到格列美脲组，其中 490 名与 487 名患者为意向治疗人群。艾塞那肽组有 203 名（41%）患者治疗失败，格列美脲组有 262 名（54%）患者治疗失败（风险差异 12.4[95%CI 6.2-18.6]，风险比 0.748[0.623-0.899]；p=0.002）。艾塞那肽组 490 名患者中有 218 名（44%），格列美脲组 487 名患者中有 150 名（31%）达到 HbA1c 浓度小于 7%（p<0.0001），艾塞那肽组 140 名（29%）和 87 名（18%）患者达到 6.5%及更低的 HbA1c 浓度（p=0.0001）。与接受格列美脲治疗的患者相比，接受艾塞那肽治疗的患者体重明显下降（p<0.0001）。每个治疗组各有 5 名患者因与治疗无关的原因死亡。与格列美脲组相比，艾塞那肽组报告有症状（p<0.0001）、夜间（p=0.007）和非夜间（p<0.0001）低血糖的患者明显较少。在治疗的最初 6 个月，因不良反应（主要是胃肠道）而停药的患者在艾塞那肽组明显高于格列美脲组（p=0.0005），但此后则不然。
这些发现为艾塞那肽与格列美脲治疗单独使用二甲双胍血糖控制不佳的 2 型糖尿病患者提供了血糖控制恶化的证据。
礼来公司；Amylin 制药公司。
